Occlusion Of Left Anterior Descending Artery Research Articles

Ischemia does not provoke the full immune training repertoire in human cardiac fibroblasts.

Trained immunity of monocytes, endothelial, and smooth muscle cells augments the cytokine response to secondary stimuli. Immune training is characterized by stabilization of hypoxia-inducible factor (HIF)-1α, mTOR activation, and aerobic glycolysis. Cardiac fibroblast (CF)-myofibroblast transition upon myocardial ischemia/reperfusion (I/R) features epigenetic and metabolic adaptations reminiscent of trained immunity. We assessed the impact of I/R on characteristics of immune training in human CF and mouse myocardium. I/R was simulated in vitro with transient metabolic inhibition. CF primed with simulated I/R or control buffer were 5days later re-stimulated with Pam3CSK for 24h. Mice underwent transient left anterior descending artery occlusion or sham operation with reperfusion for up to 5days. HIF-regulated metabolic targets and cytokines were assessed by qPCR, immunoblot, and ELISA and glucose consumption, lactate release, and lactate dehydrogenase (LDH) by chromogenic assay. Simulated I/R increased HIF-1α stabilization, mTOR phosphorylation, glucose consumption, lactate production, and transcription of PFKB3 and F2RL3, a HIF-regulated target gene, in human CF. PGK1 and LDH mRNAs were suppressed. Intracellular LDH transiently increased after simulated I/R, and extracellular LDH showed sustained elevation. I/R priming increased abundance of pro-caspase-1, auto-cleaved active caspase-1, and the expression and secretion of interleukin (IL)-1β, but did not augment Pam3CSK-stimulated cytokine transcription or secretion. Myocardial I/R in vivo increased abundance of HIF-1 and the precursor and cleaved forms of caspase-1, caspase-11, and caspase-8, but not of LDH-A or phospho-mTOR. I/R partially reproduces features of immune training in human CF, specifically HIF-1α stabilization, aerobic glycolysis, mTOR phosphorylation, and PFKB3 transcription. I/R does not augment PGK1 or LDH expression or the cytokine response to Pam3CSK. Regulation of PAR4 and inflammasome caspases likely occurs independently of an immune training repertoire.

Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation.

Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction. We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function. Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle. We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.

Validation of mitochondrial function measurements in permeabilized myocardial tissue from porcine left ventricular specimens with ischemia/reperfusion

Abstract Background Mitochondrial function is critical to myocardial ischemia/reperfusion injury and cardioprotection. The measurement of mitochondrial function in isolated mitochondria requires cardiac specimens of about 300 mg and is therefore only possible at the end of an animal experiment or during cardiosurgical interventions in humans. As an alternative, permeabilized myocardial tissue can be used for quantification of mitochondrial respiration in small myocardial specimens of about only 2-5 mg, which can be retrieved by sequential biopsies in animal experiments and during cardiac catheterization in humans. Whether or not mitochondrial dysfunction during ischemia/reperfusion is reflected to the same extent in saponin-permeabilized myocardial tissue specimens (PMT) and in isolated mitochondria is still unclear. Purpose We attempted to validate measurements of mitochondrial respiration from PMT by comparison to those from isolated mitochondria in left ventricular myocardium from anesthetized pigs undergoing coronary occlusion/reperfusion. Methods Göttingen open-chest, anesthetized minipigs (n=10) were subjected to 60 min distal left anterior descending artery occlusion and 180 min reperfusion. At the end of reperfusion, PMT and isolated mitochondria were prepared from remote and ischemic/reperfused myocardium. Baseline, adenosine diphosphate-stimulated complex I (without/with cytochrome c, to account for absence or presence of the outer mitochondrial membrane integrity) and complex IV respiration was measured at 37°C during magnetic stirring using a high-resolution respirometer. Mitochondrial respiration in PMT and isolated mitochondria was normalized to protein content and the content of the mitochondrial marker protein cytochrome c oxidase 4. Results Mitochondrial respiration measurements in PMT and isolated mitochondria correlated well (Figure 1A) and agreed well in Bland-Altman plot (Figure 1B). While baseline respiration in PMT was somewhat higher than that in isolated mitochondria (Figure 2A), mitochondrial dysfunction during ischemia/reperfusion was equally reflected in PMT and isolated mitochondria (Figure 2B &amp; 2C). Complex IV respiration was not different between remote myocardium and ischemic/reperfused myocardium, independently of the preparation, indicating a comparable amount of viable mitochondria (Figure 2D). Conclusion Mitochondrial function measurements in PMT can substitute for that in isolated mitochondria to reflect their dysfunction in ischemia/reperfusion. Thus, mitoprotective strategies targeting ischemia/reperfusion injury in small tissue samples and also in human myocardial biopsies can be followed in PMT.Figure 1Figure 2

Abstract 15205: miR-132 Inhibition Improves Myocardial Strain in a Large Animal Model of Chronic Adverse Remodeling

Background: MicroRNAs (miRNAs) are transcriptional regulators and essential drivers of heart failure (HF). The miR-132 is necessary and sufficient to progress adverse cardiac remodeling. The strong effects are exhibited by, amongst others, cardiomyocyte hypertrophy and calcium signaling impairment. Treatments directly targeting the roots of the disease are scarce, but miR-132 inhibition by CDR132L, a rationally designed synthetic oligonucleotide, significantly improves cardiac dysfunction in HF early after myocardial infarction (MI). Rational: The aim of the current study was to gain further data on myocardial function and efficacy of CDR132L by analyzing left ventricular (LV) and atrial (LA) wall motion by serial cardiac magnetic resonance (cMRI) strain imaging in a clinically relevant large animal (pig) model of chronic HF. Methods and Results: Mangalica pigs (n=15) were randomized 1-month post-MI, initiated by left anterior descending artery occlusion followed by reperfusion as a chronic model of post-MI HF. Animals received CDR132L over 5 months by monthly intravenous treatments with 5 mg/kg. LV and LA strain parameters were deteriorated after MI over time but significantly ameliorated by CDR132L treatment, compared to placebo. Strain parameters showed significant correlations with pharmacodynamic measures such as left-ventricular ejection fraction, NT-proBNP and cardiac interstitial fibrosis in remodeling hearts 6 months post-MI. Conclusions: LV and LA motion and contractility were improved by repeated dosing of CDR132L with monthly frequency in a large animal model of chronic post-MI HF. The results highlight the translational value and usability of MRI-based cardiac strain imaging in HF drug development and support further clinical development of CDR132L.

Colchicine added to standard therapy further reduces fibrosis in pigs with myocardial infarction.

The anti-inflammatory drug colchicine improves the outcome of patients with myocardial infarction (MI). As an intense inflammatory and fibrotic response after MI may lead to scar expansion and left ventricular (LV) remodeling, the clinical benefit of colchicine could be related to a positive effect on the infarct scar and LV remodeling. Pigs underwent left anterior descending artery occlusion through an angioplasty balloon for 90 min and were then randomized into two groups: standard therapy [ACE inhibitor, beta blocker, mineralocorticoid receptor antagonist (MRA), aspirin] plus colchicine (n = 14) or standard therapy alone (n = 13). The pigs were treated for 30 days and underwent two cardiac magnetic resonance (CMR) scans at 72 h and 30 days. The pigs were then sacrificed the day after the second CMR. The primary efficacy end point was the extent of fibrosis in the infarct zone (calculated on eight samples from this zone and averaged). In the hearts explanted after 31 days, pigs in the colchicine group had less fibrosis in the infarct zone than the other animals [41.6% (20.4-51.0) vs. 57.4% (42.9-66.5); P = 0.022]. There was a trend toward a higher myocardial salvage index (MSI; an index of the efficacy of revascularization) in pigs on colchicine (P = 0.054). Conversely, changes in LV volumes, ejection fraction and mass did not differ between groups. Colchicine therapy for 1 month after reperfused MI further reduces myocardial fibrosis when added to standard therapy, while it does not have additional effects on LV remodeling.

Pre-arterialization of coronary veins prior to retroperfusion of ischemic myocardium: percutaneous closure device.

Chronic coronary retroperfusion to treat myocardial ischemia has previously failed due to edema and hemorrhage of coronary veins suddenly exposed to arterial pressures. The objective of this study was to selectively adapt the coronary veins to become arterialized prior to coronary venous retroperfusion to avoid vascular edema and hemorrhage. In 32 animals (Group I = 19 and Group II = 13), the left anterior descending (LAD) artery was occluded using an ameroid occlusion model. In Group I, the great cardiac vein was blocked with suture ligation (Group IA = 11) or with occlusion device (Group IB = 8) to arterialize the venous system within 2 weeks at intermediate pressure (between arterial and venous levels) before a coronary venous bypass graft (CVBG) was implemented through a left internal mammary artery (LIMA) anastomosis. Group II only received the LAD artery occlusion and served as control. Serial echocardiograms showed recovery of left ventricular (LV) function with this adaptation-arterialization approach, with an increase in ejection fraction (EF) in Group I from 38% ± 5% after coronary occlusion to 53% ± 7% eight weeks after CVBG, whereas in Group II the EF never recovered (41% ± 2%-33% ± 7%). The remodeling of the venous system not only allowed restoration of myocardial function when CVBG was implemented but possibly promoted a novel form of "collateralization" between the native arterioles and the newly arterialized venules, which revascularized the ischemic myocardium. These findings form a potential rationale for a venous arterialization-revascularization treatment for the refractory angina and the "no-option" patients using a hybrid percutaneous (closure device for arterialization)/surgical approach (CVBG) to revascularize the myocardium.

Electrocardiographic acute inferior myocardial infarction with right ventricle involvement due to acute thrombotic left anterior descending occlusion in a patient with atrial septal defect

Detecting the anatomic location of the lesion with the help of electrocardiography (ECG) is an important and time-saving decision in cases of acute ST-segment elevation myocardial infarction. However, it can be difficult in some patients with different coronary anatomies or underlying structural heart diseases. Here, we reported a 34-year-old male patient with an underlying atrial septal defect (ASD) who presented with acute inferior myocardial infarction with right ventricle (RV) involvement due to acute thrombotic left anterior descending artery occlusion.

History of cerebrovascular events is associated with a higher risk of significant left anterior descending artery stenosis

Abstract Funding Acknowledgements Type of funding sources: None. Background Acute coronary syndrome (ACS) remains a frequent cause of hospital admission, with its prognosis depending on many factors, one being the location of the culprit lesion. It is established that anterior myocardial infarction, caused mostly by left anterior descending artery occlusion is associated with a worse prognosis and higher morbimortality. Therefore, identifying patients at a higher risk of significant LAD lesions could potentially impact outcomes. Purpose We aim to identify if having personal history of cerebrovascular events could be related to more severe LAD stenosis. Methods We retrospectively analysed a population of 988 patients (L) admitted with ACS and divided them into two groups: those who had significant stenosis of the left anterior descending artery (LAD) documented in coronary angiography, defined as a stenosis above 50% (L1), and those who had no significant stenosis of the LAD (L2), which included those with no stenosis or stenosis under 50%. We then compared the prevalence of previous cerebrovascular events, defined as stroke or TIA, between both groups. Age, sex, personal history of smoking, hypertension, dyslipidaemia and diabetes mellitus were also documented. Results L1 was comprised of 553 patients (56,0% of the population). When comparing between groups, results show that L1 had a significantly higher prevalence of previously documented stroke or TIA (1,4% vs 0,2%, p=0,026; odds ratio: 7,628, 95% CI [0,922; 63,120]) than L2. Regarding age, sex and history of hypertension, dyslipidaemia and diabetes, there were no relevant differences and no impact on the severity of the LAD stenosis. Conclusions Patients with ACS and previous history of cerebrovascular events have a sevenfold-increased risk of having significant LAD stenosis on coronary angiography. This could potentially impact pre-procedure risk stratification and timing of percutaneous intervention.

Puerarin protects against myocardial ischemia/reperfusion injury by inhibiting ferroptosis.

This study investigated whether pretreatment with puerarin could alleviate myocardial ischemia/reperfusion (I/R) injury in a cardiomyocyte oxygen-glucose deprivation and reoxygenation (OGD/R) model and in a mouse I/R injury model. For in vitro experiments, H9C2 cells were divided into control, erastin, OGD/R, OGD/R + puerarin, and OGD/R + ferrostatin (Fer)-1 groups. Parameters related to ferroptosis included levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), ATP, reactive oxygen species (ROS), glutathione (GSH), prostaglandin endoperoxide synthase (Ptgs) 2 mRNA, glutathione peroxidase (GPX) 4 protein and iron. In H9C2 cells, puerarin or Fer-1 pretreatment reduced ferroptosis, as indicated by decreased ROS and increased GSH, ATP levels. In vivo, wild-type mice were randomly divided into sham, I/R + vehicle, I/R + puerarin, and IR + Fer-1 groups. The I/R model was established by 30 min of left anterior descending artery occlusion followed by 24 h of reperfusion. Pretreatment with puerarin or Fer-1 significantly reduced infarct size in I/R mice, and decreased the activities of Myeloperoxidase (MPO) and cardiac enzymes such as creatine kinase MB isoenzyme (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) compared to those in the vehicle-treated group. Puerarin also reduced the production of MDA and 4-HNE, reduced the mRNA expression of Ptgs2 mRNA, and increased GPX4 protein expression. These results showed that puerarin exerted protective effects against myocardial I/R injury by inhibiting ferroptosis and inflammation, and therefore may have therapeutic potential for treatment of acute myocardial infarction.

PS-B02-5: NICORANDIL SUPPRESSES ISCHEMIA-INDUCED CARDIAC NOREPINEPHRINE ENHANCEMENT AND VENTRICULAR ARRHYTHMIAS IN PRESSURE OVERLOAD-INDUCED HYPERTROPHIC HEARTS.

Objective: Ventricular arrhythmias are a common cause of sudden death in acute myocardial infarction (MI) and hypertension is a major risk factor of MI. Nicorandil, an ATP sensitive potassium channel (KATP) opener, is usually used in the treatment of acute MI. KATP expresses in nerve terminals as well as cardiomyocytes and KATP in nerve terminals regulates norepinephrine release. The effects of nicorandil on ischemic myocyte are fully defined. On the other hand, the roles of nicorandil on ischemic norepinephrine release in hypertrophic cardiac tissue has remained unexplored. We examined whether nicorandil suppressed interstitial norepinephrine level and ventricular arrhythmia during acute ischemia in chronic pressure overload-induced hypertrophic hearts. Design and Methods: Rats were divided into two groups: abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and function were examined using echocardiography and hemodynamic measurements, and cardiac tissues were stained with hematoxylin and eosin and Sirius Red for histological examinations. In other rats, 4 weeks after constriction myocardial ischemia was induced by the left anterior descending artery occlusion for 100 minutes in the presence or absence of intravenous infusion of nicorandil. Cardiac interstitial norepinephrine concentration in ischemic region was measured using the microdialysis method. Ventricular arrhythmias were monitered by ECG during whole ischemic period. Results: Four weeks after constriction, remarkable left ventricular wall thickening and diastolic dysfunction were observed in AAC group. In histological examination, remarkable myocyte hypertrophy and interstitial fibrosis were observed in AAC group. Before ischemia, ventricular arrhythmia was not found in both groups. Number of ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, was increased in early ischemic period (−20 min) in both groups, and was grater in AAC group. Before ischemia, interstitial norepinephrine concentration in cardiac tissue was higher level in AAC group than in Sham group, and ischemia increased norepinephrine concentration in both groups. Nicorandil administration in ischemic period significantly suppressed the number of ventricular arrhythmias and abolished the ventricular tachycardia and fibrillation without hemodynamic alterations in hypertrophic hearts. Nicorandil also attenuated epinephrine enhancement in acute ischemic period in hypertrophic hearts. Conclusion: Ischemia-induced ventricular arrhythmias were more frequent and severe in hypertrophic hearts and associated with high interstitial norepinephrine concentration. Nicorandil suppressed ischemia-induced interstitial norepinephrine release by neuronal KATP opening, which attenuated ventricular arrhythmias in pressure overload-induced hypertrophic hearts.

UpStreAm doxycycline in ST-eLeVation myocArdial infarction: targetinG infarct hEaling and ModulatIon (SALVAGE-MI trial).

Experimental studies demonstrate protective effects of doxycycline on myocardial ischaemia-reperfusion injury. The trial investigated whether doxycycline administered prior to reperfusion in patients presenting with ST-elevation myocardial infarction (STEMI) reduces infarct size (IS) and ameliorates adverse left ventricular (LV) remodelling. In this randomized, double-blind, placebo-controlled trial, patients presenting with STEMI undergoing primary percutaneous coronary intervention (PPCI) were randomized to either intravenous doxycycline or placebo prior to reperfusion followed by 7 days of oral doxycycline or placebo. The primary outcome was final IS adjusted for area-at-risk (fIS/AAR) measured on two cardiac magnetic resonance scans ∼6 months apart. Of 103 participants, 50 were randomized to doxycycline and 53 to placebo and were matched for age (59 ± 12 vs. 60 ± 10 years), male sex (92% vs. 79%), diabetes mellitus (26% vs. 11%) and left anterior descending artery occlusion (50% vs. 49%), all P > 0.05. Patients treated with doxycycline had a trend for larger fIS/AAR [0.79 (0.5-0.9) vs. 0.61 (0.47-0.76), P = 0.06], larger fIS at 6 months [18.8% (12-26) vs. 13.6% (11-21), P = 0.08], but similar acute IS [21.7% (17-34) vs. 19.4% (14-27), P = 0.19] and AAR [26% (20-36) vs. 24.7% (16-31), P = 0.22] compared with placebo. Doxycycline did not ameliorate adverse LV remodelling [%Δend-diastolic volume index, 1.1% (-3.8-8.4) vs. -1.34% (-6.1-5.8), P = 0.42] and was independently associated with larger fIS (regression coefficient = 0.175, P = 0.03). Doxycycline prior to PPCI neither reduced IS acutely or at six months nor attenuated adverse LV remodelling. These data raise safety concerns regarding doxycycline use in STEMI for infarct modulation and healing.

Abstract 15228: Manganese-Enhanced MRI (MEMRI) Determines the Mechanistic Efficacy of Exosome Therapy in a Porcine Myocardial Infarction Model

Introduction: Transplantation of exosomes from mesenchymal stem cells (MSCs) and induced pluripotent stem cell derived cardiomyocytes (iCMs) improves heart function after myocardial infarction (MI). However, imaging methods have not been established to assess the mechanism of these treatments. Contrast imaging with gadolinium delayed-enhancement MRI (DEMRI) allows non-specific quantification of myocardial fibrosis. In contrast, MEMRI demonstrates active uptake of manganese into intracellular space by the viable cardiomyocytes via L-type calcium channel. MEMRI delineates the level of cellular metabolism and identifies the recovery of the injured but viable cardiomyocytes in the peri-infarct region (PIR). Hypothesis: MEMRI reflects the mechanistic efficacy of cell therapy. Methods: Yorkshire swine were subject to percutaneous proximal left anterior descending artery occlusion for 1 hour. Ten 500ul injections containing 5 x 10 11 exosomes isolated from MSCs and iCMs were delivered transendocardially to the PIR. Four weeks after injury, left ventricular ejection fraction (LVEF), and myocardial scar/viability were measured. DEMRI and MEMRI delineated the PIR to quantify the effects of exosomes. Results: The LVEF of PBS (control), MSC-exosome, and iCM-exosome groups was 18.66% ± 4.23, 27.46% ± 6.16, and 29.5% ± 3.96*, respectively (*p&lt;0.05). The % contrast enhancement by DEMRI over total LV volume were 29.38% ± 4.86, 28.76% ± 5.02, and 29.58% ± 5.55, respectively. Meanwhile, the % contrast nulling (CN, non-viable) by MEMRI were 20.51% ± 3.86, 9.53% ± 1.99, and 7.31% ± 2.62*, respectively (*p&lt;0.01). mRNA seq of the porcine myocardium and subsequent gene ontology and KEGG analyses demonstrated significant differential gene expression of iCM-exosome group related to calcium regulation (adenylate cyclase 7, 3.30-fold change) and sarcoplasmic reticulum calcium ion transport (chemokine receptor 5, 3.15-fold change). Conclusions: The % CN reduction of MEMRI reflects improved cardiomyocyte metabolism and calcium handing by exosome therapy. The underlying mechanism and functional improvement are identified by MEMRI.

Myocardial perfusion recovery induced by an α-calcitonin gene-related peptide analogue

BackgroundEndogenous calcitonin gene-related peptide (CGRP) induces cardioprotective effects through coronary vasodilation. However, the systemic administration of CGRP induces peripheral vasodilation and positive chronotropic and inotropic effects. This study aims to examine the net effect on coronary perfusion of the systemically administered α-calcitonin gene-related peptide analogue, SAX, in rats during myocardial infarction. MethodsForty Sprague-Dawley rats underwent myocardial infarction. Following left anterior descending artery occlusion, [99mTc]Tc-sestamibi was administered to determine the myocardial perfusion before treatment. Twenty minutes, 24 and 48 h after [99mTc]Tc-sestamibi injection, the rats were treated with either SAX or placebo. Final infarct size was determined three weeks later by [99mTc]Tc-sestamibi SPECT/CT scan. ResultsThirty-one rats survived the surgery and 20 completed the follow-up SPECT/CT scan (SAX n = 12; Placebo n = 8). At baseline, there was no difference in size of perfusion defect between the groups (P = .88), but at follow-up the SAX group had improved myocardial recovery compared to the placebo group (P = .04), corresponding to a relative perfusion recovery of 55% in SAX-treated rats. ConclusionThe CGRP analogue, SAX, has a cardioprotective effect in this rat model of myocardial infarction, improving myocardial perfusion recovery after chronic occlusion of the coronary artery.

Targeting DNA methylation can reduce cardiac injury associated with ischemia reperfusion: One step closer to clinical translation with blood-borne assessment.

Ischemia reperfusion (I/R) injury is one of the main clinical challenges for cardiac surgeons. No effective strategies or therapy targeting the molecular and cellular mechanisms to reduce I/R exists to date, despite altered gene expression and cellular metabolism/physiology. We aimed to identify whether DNA methylation, an unexplored target, can be a potential site to curb I/R-associated cell death by using the left anterior descending artery occlusion model in male Wistar rats. I/R rat heart exhibited global DNA hypermethylation with a corresponding decline in the mitochondrial genes (PGC-1α, TFAM, POLG, ND1, ND3, ND4, Cyt B, COX1, and COX2), antioxidant genes (SOD2, catalase, and Gpx2) and elevation in apoptotic genes (Casp3, Casp7, and Casp9) expression with corresponding changes in their activity, resulting in injury. Targeting global DNA methylation in I/R hearts by using its inhibitor significantly reduced the I/R-associated infarct size by 45% and improved dysferlin levels via modulating the genes involved in cell death apoptotic pathway (Casp3, Casp7, and PARP), inflammation (IL-1β, TLR4, ICAM1, and MyD88), oxidative stress (SOD1, catalase, Gpx2, and NFkB) and mitochondrial function and its regulation (MT-ND1, ND3, COX1, ATP6, PGC1α, and TFAM) in the cardiac tissue. The corresponding improvement in the genes’ function was reflected in the respective hearts via the reduction in apoptotic TUNEL positive cells and ROS levels, thereby improving myocardial architecture (H&E staining), antioxidant enzymes (SOD, catalase activity) and mitochondrial electron transport chain activities and ATP levels. The analysis of blood from the I/R animals in the presence and absence of methylation inhibition exhibited a similar pattern of changes as that observed in the cardiac tissue with respect to global DNA methylation level and its enzymes (DNMT and TET) gene expression, where the blood cardiac injury markers enzymes like LDH and CK-MB were elevated along with declined tissue levels. Based on these observations, we concluded that targeting DNA methylation to reduce the level of DNA hypermethylation can be a promising approach in ameliorating I/R injury. Additionally, the blood-borne changes reflected I/R-associated myocardial tissue alteration, making it suitable to predict I/R-linked pathology.

Ultrasound-guided injection of botulinum toxin type A blocks cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic myocardial infarction

Strategies to improve various cardiovascular diseases by blocking cardiac sympathetic ganglion have been increasingly available currently. Botulinum toxin type A (BTA), a typical neurotoxin, has been shown to block neural transmission in a safe and long-lasting manner. The aim of the present preclinical study was to assess the efficacy of BTA microinjection to alleviate cardiac remodeling after chronic myocardial infarction (MI) by blocking cardiac sympathetic ganglion in a canine model. Beagles were randomly divided into a control group (saline microinjection with sham surgery), an MI group (saline microinjection with MI), and an MI + BTA group (BTA microinjection with MI). Ultrasound-guided percutaneous BTA or saline injection into the left stellate ganglion (LSG) was performed followed by MI induction via left anterior descending artery occlusion (LADO) or sham surgery. After 30 days, electrocardiography, Doppler echocardiography, LSG function, neural activity, and ventricular electrophysiological detection were performed in all experimental dogs. At the end, LSG and ventricular tissues were collected for further detection. BTA treatment significantly inhibited LSG function and neural activity and improved heart rate variability. Additionally, BTA application alleviated ventricular remodeling, ameliorated cardiac function, and prevented ventricular arrhythmias after 30-day chronic LADO-induced MI. Ultrasound-guided percutaneous microinjection of BTA can block cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic LADO-induced MI. Ultrasound-guided BTA microinjection has potential for clinical application as a novel cardiac sympathetic ganglion blockade strategy for MI.

An unusual culprit lesion in acute coronary syndrome: In stent-restenosis of a subclavian artery stent

A 73-year old man with past medical history of coronary artery bypass grafting in 2012 and subclavian artery stenting in 2021 was scheduled for an ophthalmologic minor surgery requiring conscious sedation. During the surgery, he developed hemodynamic instability and shortness of breath requiring the conversion to general anesthesia with mechanical ventilation. An electrocardiogram was immediately realized revealing deep negative T waves in all the precordial leads. Elevated troponin level confirmed the diagnosis of non-ST elevation myocardial infarction. Urgent coronary artery angiography revealed a known left coronary system with a chronic Left Anterior Descending (LAD) artery occlusion, a chronic occlusion of the distal circumflex artery and a severe stenosis of left main stem. The right coronary artery presented a significant and calcified stenosis on its mid part. The two venous grafts on the obtuse marginal and the posterolateral artery were both patent. The left subclavian artery could not be crossed to selectively film the left internal mammary artery and an angiogram revealed a tight stenosis in the previous stented segment, limiting the blood flow in the left internal mammary artery. Careful review of the in-stent restenosis suggested neointimal hyperplasia and stent fracture, as detected by stentboost imaging.

&lt;i class="fa fa-video-camera" aria-hidden="true"&gt;&lt;/i&gt; Quince a�os de intervencionismo percut�neo de la oclusi�n total coronaria cr�nica. Experiencia, resultados y pron�stico cl�nico

Introduction and objectives: Chronic total coronary occlusion (CTO) is often a complex entity to deal with through a percutaneous coronary intervention, and the clinical benefits of successful recanalization still remain uncertain. Most registries feature data in limited time periods and do not reflect the impact that specific dedicated programs have on recanalization. Our study evaluates the results of a CTO program on a long-term period of time. Methods: All patients’ CTOs treated with percutaneous coronary interventions at our center from 2002 through 2017 were prospectively included in the registry. The clinical, angiographic and procedural data were collected, and clinical follow-up was conducted. Three consecutive periods of time were considered for the analysis of temporal trends. Results: A total of 424 CTOs (408 patients) were included. In 339 patients (80%) the procedure was successful. The rate of success increased over time, from 57% in 2002-2006 to 87% in 2012-2017 (P = .001). The most important independent predictor of procedural failure was lesion tortuosity. After a median follow-up of 39.7 months, the rates of major adverse cardiovascular events and cardiovascular mortality in success vs failed groups were 13.9% vs 24.7% (P = .015) and 3.6% vs 14.1% (P = .001), respectively. These were the independent predictors of cardiovascular mortality: chronic kidney disease, left anterior descending artery occlusion, and procedural failure. Conclusions: Our series shows a high rate of success in CTO recanalization, which has increased over the last few years due to greater expertise and improved program-specific technical advances. Several angiographic and procedural variables have been identified as predictors of failure. Successful procedures, especially on the left anterior descendent coronary artery, were associated with lower rates of cardiovascular mortality.

Impact of intracoronary reteplase during primary percutaneous coronary intervention on infarct size in large anterior myocardial infarction: rationale and design of the RECOVER II trial

Thrombus embolization and microvascular obstruction during percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) is commonly detected, which causes inadequate myocardial perfusion and elevated infarct size. An approach with low-dose intracoronary fibrinolytic treatment for reducing distal embolization and improving myocardial reperfusion in high-risk STEMI cases remains controversial. The RECOVER II study represents a multicenter, randomized, double-blind, parallel-group trial assessing low-dose adjunctive intracoronary reteplase during primary PCI in individuals with large anterior myocardial infarction and thrombus determined by angiography. The trial will enroll 306 cases who present within 12 h following STEMI for proximal or mid left anterior descending artery occlusion undergoing primary PCI. Cases will be randomized to receive a bolus intracoronary reteplase at 9 mg or 18 mg vs. placebo. The drug will be delivered over 2 minutes proximal to culprit lesions with an intracoronary catheter early after wire-crossing and before thrombus aspiration or balloon dilation. The primary outcome will be infarct size assessed by late gadolinium-enhanced magnetic resonance imaging (MRI) (% of left ventricular mass) on day 7 after enrollment. Secondary outcomes will include the amount of microvascular obstruction and myocardial salvage index examined via MRI on day 7, angiographic measures of reperfusion [Thrombolysis in Myocardial Infarction (TIMI) coronary flow grade, TIMI frames count and myocardial blush grade], incidence of complete ST-segment resolution at 2 hours after reperfusion, area under the curve for troponin T, and rates of major adverse cardiovascular events at 30 days. RECOVER II will determine whether the addition of low-dose intracoronary reteplase early after wire-crossing as an adjunct to reperfusion treatment reduces infarct size in individuals with large anterior myocardial infarction. ClinicalTrials.gov Identifier: NCT04571580.

P59 A COMPLEX PCI IN A CARDIOGENIC SHOCK NSTEMI PATIENT NEEDING PTA AND LEFT VENTRICLE ASSISTANCE

Abstract A 72–years–old man, smoker, type 2 DM and hypertension in history, was admitted for NSTEMI complicated by cardiogenic shock; Echocardiogram revealed LV dilatation with severe disfunction (EF 20%), moderate mitral regurgitation; he started inotropic support and high dose diuretics, then he needed dialysis and positioning of a temporary PM. Coronary angiography revealed chronic total occlusion (CTO) of the left anterior descending artery (LADA) and CTO of the right coronary artery (RCA). A first CTO PCI procedure was attempted for the LADA occlusion, with the support of IABP, using an antegrade approach, polimeric wire (ASAHI Fielder) and more penetrating ones (ASAHI Gaia I and II), unable to gain the true lumen beyond the occlusion. A second attempt was planned, with the support of Impella CP device for left ventricle assistance; due to critical stenosis in the right common iliac artery, a PTA with stenting (8/38 mm) was preparatory for that. For the second attempt a dual coronary approach was prepared (6 F Amplatz left 1,0 for RCA and 7 F XB 3,5 for left coronary artery); at first a novel antegrade attempt was pursued with a step–up technique (ASAHI wires: Gladius, Gaia I, II and III, Conquest pro), ineffective to reach the true lumen distally the occlusion. The retrograde approach was then pursued, through a collateral originating from the acute marginal branch of the RCA to the distal segment of LADA, using the Caravel microcatheter with ASAHI wires Sion blue, Sion black, Suoh 03, effective to reach the distal cap of the occlusion, this one passed by the Gladius wire. The ASAHI RG3 externalization wire (330 mm) was then used, entering from the radial access and the amplatz catheter for the RCA, reaching the XB catheter in the left coronary artery through a Guideliner extension catheter, and externalized in the femoral access. IVUS analysis was then used to confirm good wire position and the vessel calibers, so pre–dilatation was done and 3 drug–eluting stents were implanted (2,25/23 + 3,25/38 + 3,5/18 mm) distal–to–proximal overlap, with final post–dilatation, obtaining a good final result on angiography and IVUS. During the 4–hours procedure clinical condition was stable and Impella was removed with a rapid weaning; the double pre–mounted Proglide device was used for femoral hemostasis. 5 days after the patient was discharged, II–III NYHA class, 25% EF. At the 3 months f–up he was asymptomatic in good clinical condition, 30% EF, he refused ICD implant.

Patterns of Cardiac Rupture in Blunt Cardiac Injuries and Coronary Artery Disease: A Retrospective Autopsy Study

Cardiac rupture is the most severe form of blunt chest injury and coronary artery disease and that leads to a devasting medical emergency, Becker and colleagues identified three types of myocardial rupture, in Govt Stanley medical college and hospital, 2017-2019 cases with the postmortem findings and hospital records suggestive of cardiac rupture, were studied retrospectively and the Information were collected and analyzed. In the retrospective study population 426 cases had blunt chest trauma in that cardiac rupture seen in 28 cases amongst Becker type I rupture seen in 26 cases and type II rupture seen in 2 cases. Amongst 792 cases of coronary artery disease with myocardial infarction 13 cases had cardiac rupture in that Beckers type I rupture noted in 5 cases and type II were noted in 8 cases. Beckers type III rupture cases were not presented in the retrospective study population. Male cases were predominantly seen in both blunt chest injuries and in coronary artery disease and most of the cases were in the age group of 31-60 years. Among blunt chest injury traffic accidents were most common cause for cardiac rupture and in coronary artery disease left anterior descending artery occlusion was the most common cause for cardiac rupture, In the present study it has been proved that a diseased heart is more susceptible to traumatic injury than a normal one. The diseased heart is more likely to rupture at the fragile myocardium sites ,The presence of fatal cardiac trauma in head on collision cases emphasizes the utility of safety belts while driving. The present study is undertaken to identify the exact pathophysiology and bio mechanism of cardiac rupture